Quercetin ameliorates thioacetamide-induced hepatic fibrosis and oxidative stress by antagonizing the Hedgehog signaling pathway

Abstract

The Hedgehog (Hh) pathway has emerged as a potential target for effectual hepatic repair based on convincing clinical and preclinical evidence that proves its significance in regulating hepatic damage. The purpose of this study is to probe the effect of quercetin on liver fibrosis through the modulation of the Hh pathway. Healthy male Wistar rats were divided into four groups (n = 10). The control group was treated with saline, rats in the remaining three groups received twice a week intoxication with intraperitoneal injections of thioacetamide (200 mg/kg) for the induction of hepatic fibrosis for 6 weeks. After 28 days of quercetin and silymarin treatment, histological changes, serum biochemical index, antioxidant enzyme activity, key mediators of Hh pathway and inflammation were analyzed. Serological analysis showed statistically improved cholesterol, H.D.L-Cholesterol, and L.D.L-Cholesterol in the treatment groups. Superoxide dismutase and glutathione levels were found to be increased after the treatment with quercetin and silymarin. mRNA expression of important mediators of the Hh signaling, and inflammation including Shh, Ihh, Ptch-1, Smo, Hhip, Gli-3, TNF-α, NFκ-β, and Socs-3 were significantly downregulated after the use of quercetin and silymarin. Quercetin also minimized the thioacetamide-induced histopathological changes, as confirmed by a lower degree of hepatic lobule degeneration, the intralobular occurrence of inflammatory cells, and a lower degree of hepatocytic necrosis. Sudan Black B staining showed remarked lipids improvements in the treatment groups. Taken together, these findings demonstrate that quercetin could ameliorate hepatic fibrosis by antagonizing the hedgehog pathway and also suggest the hedgehog pathway as a potential therapeutic target for the treatment of liver fibrosis.

Keywords: Hedgehog pathway; hepatic fibrosis; oxidative stress; quercetin; silymarin.